By the end of 2007, about 33.2 million people in the world are living with human immunodeficiency virus (HIV) infection and more than 25 million people have died of Acquired Immunodeficiency Syndrome (AIDS). Therefore, it is urgently needed to discover and develop new therapeutic strategies against HIV infection. So far, 28 anti-HIV drugs have been approved by the Food and Drug Administration of the United States to treat people infected with HIV, including 15 reverse transcriptase inhibitors (RTIs), 10 protease inhibitors (PIs), one integrase inhibitor (II), and two entry inhibitors (EIs). All the RTIs, PIs, and II inhibit HIV replication after the virus enters the host cells. The two EIs can block HIV entry into the host cell, but they cannot inactivate virus before HIV attaches to the target cell.
One of the EIs is a synthetic peptide designed based on the sequence of the HIV envelope protein (Env) transmembrane subunit gp41 C-terminal heptad repeat (CHR) region, named T20 (enfuvirtide, FUZEON®), which inhibits HIV fusion with the host cell by targeting gp41. T20 inhibits HIV entry by targeting HIV envelope protein (Env) gp41, which consists of fusion peptide (FP), and N- and C-terminal heptad repeats (NHR and CHR) (FIG. 1). In the native state, gp41 is inaccessible since it is buried underneath HIV Env gp120. At the beginning of HIV infection process, gp120 binds to CD4 on the target cell, causing gp41 to change conformation: (1) FP inserts into the target cell membrane; (2) NHR associates to form an NHR-trimer, and (3) CHR interacts with NHR-trimer to form a hairpin-like six-helix bundle (6-HB) which brings the viral and cellular membranes into close proximity which is necessary for fusion. T20 and C34, another CHR peptide (CP) can bind to the viral gp41 NHR-trimer and block 6-HB formation, resulting in inhibition of HIV fusion. However, T20 cannot inactivate HIV circulating in the blood before the virus attaches to the target cell because it can only interact with HIV after the virus comes into contact with CD4 on the target cell. Because of this problem, the T20 peptide must be maintained in the blood of HIV/AIDS patients at a constant high concentration. Therefore, T20 has to be administrated by injection twice a day at 90 mg/dose, resulting in painful injection-site reactions in most patients and high cost to the patients (>$20,000/year/patient). Consequently, T20 is exorbitantly expensive for use in developing countries. Therefore, improved drugs for treating HIV infection and AIDS are needed.